Related Experiment Videos
A PAF antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep
M Solèr1, M W Sielczak, W M Abraham
1Division of Pulmonary Disease, Mount Sinai Medical Center, Miami Beach, Florida 33140.
Abstract:
We studied the effects of WEB-2086, a specific antagonist of platelet-activating factor (PAF), on the development of antigen-induced airway hyperresponsiveness and inflammation in sheep (n = 8). For these studies, airway responsiveness was determined from slopes of carbachol dose-response curves (DRC) performed at base line (prechallenge) and 2 h after Ascaris suum antigen challenges in the following three protocols: 1) antigen challenge alone (control trial), 2) WEB-2086 (1 mg/kg iv) given 30 min before antigen challenge (WEB pretreatment), and 3) WEB-2086 given 2 h after antigen challenge, immediately before the postchallenge DRC (WEB posttreatment). Airway inflammation was assessed by bronchoalveolar lavage (BAL) before antigen challenge and after the postchallenge DRC for each trial. A. suum challenge resulted in acute increases in specific lung resistance that were not different among the three trials. Antigen challenge (control trial) caused a 93% increase (P less than 0.05) in the slope of the carbachol DRC when compared with the prechallenge value. WEB pretreatment (1 mg/kg) reduced (P less than 0.05) this antigen-induced hyperresponsiveness, whereas pretreatment with a 3-mg/kg dose completely prevented it. WEB posttreatment was ineffective in blocking this hyperresponsiveness. BAL neutrophils increased after antigen challenge in the control trial and when WEB-2086 was given after antigen challenge (P less than 0.05). Pretreatment with WEB-2086 (1 or 3 mg/kg) prevented this neutrophilia. This study provides indirect evidence for antigen-induced PAF release in vivo and for a role of endogenous PAF in the modulation of airway responsiveness and airway inflammation after antigen-induced bronchoconstriction in sheep.
Insights
WEB-2086, a platelet-activating factor (PAF) antagonist, effectively reduced antigen-induced airway hyperresponsiveness and inflammation in sheep when given before antigen challenge. Post-challenge administration of WEB-2086 did not block these effects.
Area of Science:
- Immunology
- Respiratory Medicine
- Pharmacology
Background:
- Platelet-activating factor (PAF) is implicated in allergic airway inflammation and hyperresponsiveness.
- Understanding the role of endogenous PAF in vivo is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the effects of WEB-2086, a PAF antagonist, on antigen-induced airway hyperresponsiveness and inflammation in a sheep model.
- To determine the efficacy of WEB-2086 when administered before versus after antigen challenge.
Main Methods:
- Sheep were challenged with Ascaris suum antigen under three conditions: control, pretreatment with WEB-2086, and posttreatment with WEB-2086.
- Airway responsiveness was measured using carbachol dose-response curves.
- Airway inflammation was assessed via bronchoalveolar lavage (BAL) to quantify neutrophil counts.
Main Results:
- Antigen challenge significantly increased airway hyperresponsiveness and BAL neutrophils in the control group.
- Pretreatment with WEB-2086 dose-dependently reduced antigen-induced airway hyperresponsiveness and prevented neutrophilia.
- WEB-2086 administered after antigen challenge was ineffective in blocking hyperresponsiveness or inflammation.
Conclusions:
- Antigen challenge in sheep leads to PAF release, contributing to airway hyperresponsiveness and inflammation.
- Pretreatment with WEB-2086 demonstrates a protective role for endogenous PAF in modulating allergic airway responses.
- Timing of PAF antagonism is critical for therapeutic efficacy in antigen-induced airway diseases.